Antigen binding to the membrane lgR initiates the activation and maturation of the antigen-specific B cells in the peripheral lymphoid organs (Rajewsky, Nature (Lond.)., 381:751–758, 1996; Sakaguchi et al., Adv. Immunol. 54:337–392, 1993). B cells enter the outer periarterial lymphoid sheath (PALS) (Rajewsky, Nature (Lond.)., 381:751–758, 1996) and initiate costimulus-dependent interactions with specific Th cells and interdigitating dendritic cells within 48 h after immunization (MacLennan, Annu. Rev. Immunol. 12:117–139, 1994; Liu et al., Immunol. Rev. 156:111–126, 1997). Antigen-driven B cells proliferate in the outer PALS and then undergo further activation in the lymphoid follicles to establish the germinal center (herein sometimes abbreviated as GC) (Han et al., J.Immunol. 155:556–567, 1995; Jacob et al., J. Exp. Med. 176:679–687, 1992; Kelsoe, Immunity 4:107–111, 1996). Such B cells mature into large slg− centroblasts that rapidly move through the cell cycle to form the dark zone and further mature into centrocytes that express a unique surface character of PNA+B220+slgM+slgD−CD38− in the light zone of the GC (Kosco-Vilbois et al., 1997. Immunol. Today 18:225–230, 1997; Kelsoe, Immunol. Today 16:324–326, 1995; Oliver et al., J. Immunol. 158:1108–1115, 1997).
Centrocytes presumably undergo the processes of either apoptosis or affinity maturation of immunoglobulin V regions and the change process of class switching toward the lgG class antigen. Some centrocytes survive for a longer period in the lymphoid compartment as memory B cells. The other centrocytes probably migrate to the marginal zone of the GC and receive further antigenic stimulation and costimulatory signals through B cell activation molecules, such as CD40 and CD38, and receptors for various B cell stimulatory cytokines (Gray et al., J. Exp. Med., 180:141–155, 1994; Foy et al., J. Exp. Med., 180:157–163, 1994). Antigen-specific B cells further stimulated in this area probably migrate into the interstitial region of the spleen (called red pulp), where various kinds of other immune-competent cells may interact with antigen-driven B cells. Histochemical analysis in several autoimmune mice identified unique antibody-producing cells in this area which appear as plasma cells or aberrant plasma cells called Mott cells (Tarlinton et al., Eur. J. Immunol. 22:531–539, 1992; Jiang et al., J. Immunol., 158:992–997, 1997).
Autoimmunity is a phenomenon in which the impairment of self/nonself discrimination occurs frequently in the antigen-specific lymphocytes (Theofilopoulos, Immunol. Today, 16:90–98, 1995). The immune systems of various autoimmune diseases show the combinatory mechanism involving T cells and B cells (Theofilopoulos et al., Adv. Immunol., 37:269–290, 1985; Okamoto et al., J. Exp. Med. 175:71–79, 1992; Reininger et al., J. Exp. Med., 184:853–861, 1996; Theofilopoulos, et al., Immunol. Rev. 55:179–216, 1981; Watanabe-Fukunaga et al., Nature (Lond.)., 356:314–317, 1992; Takahashi et al., Cell, 76:969–976, 1994; Shlomchick et al., Nature (Lond.). 328:805–811, 1987).
NZB and NZW are the strains characterized by multiple genetic factors generating the severe autoimmune state of SLE as (NZB×NZW)F1 mice (Theofilopoulos et al., Adv. Immunol., 37:269–290, 1985; Okamoto et al., J. Exp. Med., 175:71–79, 1992; Reininger et al., J. Exp. Med., 184:853–861, 1996; Theofilopoulos et al., Immunol. Rev., 55:179–216, 1981). NZB mice spontaneously generate the state of autoimmunity with the anti-red blood cell antibody that causes an autoimmune hemolytic anemia (Okamoto et al., J. Exp. Med., 175:71–79, 1992). NZW mice show an insidious autoimmune phenomenon (Reininger et al., J. Exp. Med. 184:853–861, 1996). The SLE state of (NZB×NZW)F1 mice is apparently caused by multiple genetic factors associated with T and B cells (Theofilopoulos et al., Immunol. Rev., 55:179–216, 1981). NZB mice show an apparent abnormality of B cells, but the molecular mechanism of the abnormal B cell activation in NZB mice remains to be elucidated.